Abstract Mast cell (MC) disorders are heterogenous, have not been well characterized, and treatment algorithms are still being developed. Recently, a new understanding of MC disease has emerged, with allergy/atopy and with rare, neoplastic mastocytosis comprising MC activation disease. The rest of the disorders are ill-defined, with complex heterogenous presentation of MC activation syndrome that features chronic multisystem inflammation with or without the atopic profile or aberrant growth of MC in various tissues. In this study, MC from patients with hereditary alpha tryptasemia (HAT), a disorder where multiple copies of the TPSAB1 gene correlate with elevated serum tryptase, are used to study the effect of MC phenotype and function on the chronic inflammatory effects in the gut. This knowledge will be utilized to develop new therapeutic uses for existing drugs that target MC functional pathways. The purpose of this multicenter Clinical and Translational Sciences Institute (CTSI) supplement is to employ current state-of-the-art techniques to elucidate differences in functional MC and inflammatory gut tissue in patients with HAT compared with control tissues, and MC in patients with inflammatory bowel disease (IBD, with and without remission), and in patients with systemic mastocytosis (SM). Mass CyTOF, RNAseq, RNAscope and phosphorylation studies will be done on both MC from lamina propria monocytic cells from right colon or ileum tissue and in gut tissue sections and from differentiated peripheral blood mononuclear cell (PBMC)-derived progenitor CD34+ cells. The results will reveal effects of these MC on the immune system and will target pathways for treatment of generalized MC disorders by utilizing the Drug Repurposing Network (DRN) at the University of New Mexico Center for Molecular Discovery, a high throughput flow cytometry- based mechanism to screen 1,280 FDA-approved compounds per patient MC or PBMC. Our hypothesis is that intestinal MC populations from HAT patients have an aberrant phenotype and function, without clonal expansion of MC as in SM, that leads to a proinflammatory state in the gut. We propose to link these HAT MC characteristics to endpoints that can be explored in the DRN. Assays will be developed to target specific pathways important in MC regulation of inflammation, for example to assay drugs targeting MGBPRX2, mTOR and JAK/STAT. Proinflammatory cytokines TNF, IL-1b, IL-6 and IFN-g will be monitored to assess the effect of high levels of tryptase on PBMC for the purposes of screening in the DRN. Through better understanding of the phenotype and function of these HAT patient gut MC, we will be able to identify personalized, mechanistic treatment algorithms that may be applicable to other MC disorders.